Emerging targets for the treatment of obesity

Rapid adaptation to a modernized lifestyle, characterized by reduced physical activity and increased consumption of a highcalorie and high-energy food, has resulted in a dramatic rise in the prevalence of being overweight and obese people in most industrialized countries. A recent report by the World Health Organization stated that there are more than one billion overweight adults worldwide, at least 300 million of whom are clinically obese. Obesity is a complex metabolic disorder affecting the whole body which can be attributed to either or both genetic background or environmental factors. Abnormalities in controlling fat content in the body are therefore defined by more than simply eating too much or exercising too little and linked to increased risk of developing a number of common, severe diseases, such as type 2 diabetes, cardiovascular disease, hypertension, stroke, cancer and nonalcoholic fatty liver, which contributes to nonalcoholic steatohepatitis. A weight loss of even a relatively small percentage (5%) has been shown to lead to significant improvement in cardiovascular risk factors in obese patients. However, lifestyle changes alone are usually insufficient to achieve and maintain even such modest weight loss in the morbidly obese. Surgery is a therapeutic option which has been shown to be effective in terms of both weight loss and reduction in morbidity and mortality related to obesity. However, the invasiveness, cost, lack of information on long-term effects and dearth of experienced bariatric surgeons have limited the use of surgery as a treatment option. Safe, effective pharmacological treatment is therefore desirable for patients with associated comorbid conditions who have been unable to maintain a healthy body weight range through diet and exercise alone. However, currently approved pharmacological therapies are limited with regard to efficacy and side-effect profiles, and are unable to achieve such weight maintenance in patients. Given these unmet needs, significant efforts are now being made to characterize molecular mechanisms of obesity that may lead to effective medical treatments and obesity prophylaxis. In this series, we review the therapeutic potential of several novel approaches and molecular targets for treating obesity, focusing on those tissues (brain, adipose, and liver) responsible for obesity. In the first minireview, Wolfgang and Lane focus on the hypothalamic area of the brain and outline the malonyl-CoA hypothesis, which targets the central regulation of energy homeostasis in the whole body. The authors also review the molecular mechanism of the neural system which detects changes in nutrient availability, body weight and adiposity status, focusing on the attractive molecular target CPT1c. The evidence shown in this article underscores the fact that the brain senses and responds to changes in nutrient availability and composition in order to moderate fat content in the body. In the second minireview, Kadomatsu et al. focus primarily on the effect of adipose tissue and liver on obesity and review the functions of novel drug targets ANGPTL2 and ANGPTL6 ⁄AGF, which are structurally similar to but functionally different from angiopoietin, in obesity and obesityrelated metabolic diseases. In the minireview, they discuss in depth that these adipocyte-derived inflammatory mediators may function as key molecules, linking obesity to systemic insulin resistance and circulating levels of these mediators may serve as a marker of obesity-induced metabolic abnormalities in the body. They also outline the function of these two targets that ANGPTL2 activates vascular inflammation and monocyte migration leading to the adipose tissue inflammation, while ANGPTL6/AGF enhances systemic energy expenditure, thereby exerting an anti-obesity effect. In the final minireview, Suwa et al. focus on the novel approach to regulation of adipocyte hyperplasia and describe the molecular functions of the drug target RMI1, which plays a pivotal role in adipocyte hyperplasia in rodents and humans. Recent evidence has indicated that increased adipocyte number is crucial in the development of severe obesity, and these authors present an overview of current findings supporting the notion that RMI1 inhibitor is a promising pharmacological option for controlling adipocyte hyperplasia. We hope that the information presented here about emerging targets functioning in the nerve center and peripheral tissues responsible for obesity will contribute to the research and development of new medicines for treating obesity as well as promoting science in general.